1. Technical Field
The present invention relates to method for creating a macro environment of buffers for delivering acid labile pharmaceuticals, stable at alkaline or near alkaline pH and oral pharmaceutical compositions of acid labile drugs, stable at alkaline or near alkaline pH and process for the preparation of the same in pharmaceutically acceptable dosage forms.
2. Background Information
Acid labile drugs such as the proton pump inhibitors tend to be unstable at acidic pH and therefore have to be formulated as enteric-coated dosage forms to prevent acid degradation. Although these drugs are stable at alkaline pH, they are destroyed rapidly as pH falls (for example, by gastric acid). Or, if the enteric-coating of the composition is disrupted (for example by chewing) resulting in degradation of the active ingredient by the gastric acid in the stomach. Upon ingestion, an acid-labile pharmaceutical compound must be protected from contact with acidic stomach secretions to maintain its pharmaceutical activity. Certain acid labile drug compositions with enteric-coating have been designed to dissolve at basic or near neutral pH to ensure that the drug is released in the proximal region of the small intestine (duodenum), not in the stomach. However, due to their pH-dependent attributes and the uncertainty of gastric retention time, in-vivo performances as well as inter and intra subject variability are very high; making it an uncertain method. Nevertheless at basic/near neutral pH also most acid-labile pharmaceutical agents are still susceptible to degradation depending on the particular pKa of the agent. Further as an acid-labile compound upon ingestion must be transferred in intact form, i.e., a non-acid degraded or reacted form, to the duodenum where the pH is near or above its pKa, the enteric-coating must be resistant to dissolution and disintegration in the stomach, that is, be impermeable to gastric fluids while residing in the stomach. Additionally, since the therapeutic onset of an enteric-coated dosage form is largely dependent upon gastric emptying time it varies between subjects. In most subjects, gastric emptying is generally an all or nothing process, and generally varies from about 30 minutes to several hours after ingestion. Thus, for a period of time following ingestion, an enteric-coated dosage form resides in the low pH environment of the stomach before moving into the duodenum. During this time, the enteric-coating may begin to dissolve, or imperfections or cracks in the coating may develop, allowing gastric acid to penetrate the coating and prematurely release drug into the stomach rather than in the small intestine. In the absence of buffering agent, an acid-labile drug that is exposed to this gastric acid is rapidly degraded and rendered therapeutically ineffective.
To overcome the disadvantages of gastric emptying time; Enteric-coated dosage forms are generally taken on an empty stomach with a glass of water. This minimizes exposure time to gastric fluid, as it ensure gastric emptying within about 30 minutes or so, and delivery of the dosage form from the stomach to the duodenum. Once in the duodenum, optimal conditions exist for the enteric-coating to dissolve and release the drug into the bloodstream where absorption of a non-acid degraded drug occurs. If food is ingested contemporaneously with the administration of an enteric-coated dosage form, gastric emptying may not only be slowed, but there is also an increase in the pH of the stomach from about pH 1 to about 5 over the next several hours, depending on, for example, the general health of the subject and the composition being administered. When the pH begins to approach 5, the enteric-coating begins to dissolve away resulting in premature release of the drug into the stomach.
In geriatric patients the gastric pH is already elevated as there is a general decline in gastric acid secretion in the stomach with aging. In such patients; enteric coated acid labile drugs are less effective. Also, when the ingested food contains any fat, gastric emptying can be delayed for up to 3 to 6 hours or more, as fat in any form combined with bile and pancreatic fluids strongly inhibits gastric emptying. Thus, as a general rule, enteric-coated dosage forms should only be ingested on an empty stomach with a glass of water to provide optimal conditions for dissolution and absorption.
To overcome the problems of enteric coated tablets; several scientists used compositions comprising large amounts of buffers (U.S. Pat. No. 6,489,346 B1, 03/2002 Jeffrey Owen Philips et al.) to prevent the degradation of acid labile drugs.
For instance, certain compositions of omeprazole contain 1100 mg of sodium bicarbonate (equivalent to 300 mg of sodium) and oral suspension contains 1680 mg of sodium bicarbonate (equivalent to 460 mg of sodium). Such formulations utilizes the concept of microenvironment pH and hence a large quantity of alkali is required to neutralize the acid in the stomach so as to protect the uncoated PPI from acid degradation and maintain intragastric pH>4 for a period of about 18 hours. The American Heart Association's recommended daily intake of sodium is 2,400 mg for a normal person and, these amounts should be taken into consideration by anyone on a sodium-restricted diet. Also Sodium bicarbonate is contraindicated in patients with metabolic alkalosis and hypocalcemia. Also such compositions weigh about 1.5-2.0 g making it difficult to swallow and hence leading to patient non-compliance. Furthermore, since, the amount of buffer depends on the pKa of the drug used, the amount of alkali required to make an immediate release composition of Pantoprazole or Rabeprazole, may be more than that required for Omeprazole. Moreover, sodium bicarbonate used in the composition has poor stability properties and decomposes by converting to carbonate and such; the decomposition is accelerated by agitation or heat. Hence, such compositions comprising large amount of buffers are also not suitable for long term usage.
All the compositions of prior art are based on the concept of micro environmental pH which is also known as virtual pH. The micro environmental or virtual pH can be said as the pH of the immediate solution when the solid is dissolved in water. This virtual membrane pH determines the extent of drug ionization and hence drug dissolution and absorption. Thus the concept of microenvironment pH questions the basics of pH partition hypothesis. It has been demonstrated that the pH of the diffusion layer at the surface of the dosage form resembles that of a saturated solution of drug and excipients in a dissolution media and represents the microenvironment pH of the system. During dissolution, medium that may eventually penetrate into the core, or during storage moisture may penetrate into the core resulting in a saturated solution of drug and excipients. If the microenvironment pH is low, it will lead to ultimate degradation of the drug.
Hence; it is seen that the compositions of acid labile drugs of prior art either use an enteric coating or high concentration of buffers or are liable to degradation in the microenvironment pH.
Therefore, there needs to be an effective method for delivering acid labile drugs such that the acid labile drugs do not degrade in the stomach.
Also, there is a need for a stable and robust composition of an immediate release composition for acid labile drugs, that is not enteric coated, uses minimal amount of buffer and it is not susceptible to degradation by acid labile drugs.
3. Object of the Invention
An object of the invention is to create a macro environment having a pH of 5 to 10 in the stomach for immediate release of acid labile compounds stable at a pH between 5 to 10.
Another object of the invention is to provide an immediate release composition of acid labile drugs that use the concept of a macro-environment pH instead of a micro-environment pH.
Yet another object of the present invention is to provide an immediate release stable pharmaceutical composition of acid labile drugs or its pharmaceutically acceptable salts and process for preparing the same.
Yet another object of the invention is to provide a composition that eliminates need for enteric coating and use of high concentration of buffers.
A further object of the invention is to provide a process for preparing the composition.